Multi-Modality As a New Pharmacological Approach for Treatment of Depression: the Role of Vortioxetine

Dimensional psychopharmacology

Multi-modality as a new pharmacological approach for treatment of depression: the role of vortioxetine La multimodalità come nuovo approccio nel trattamento della depressione: il ruolo di vortioxetina

F. Caraci1,2, G. Di Sciascio3

1 Department of Drug Sciences, Section of Pharmacology, University of Catania, Catania; 2 IRCCS Associazione Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging, Troina, Enna; 3 Hospital “Consorziale Policlinico” School of Medicine, Unit of Psychiatry, University of Bari

Summary nist of 5-HT1B receptors, an agonist of 5-HT1A receptors, and in- Recent evidence, such as that from the STAR-D study, have hibitor of the serotonin transporter. The combination of 5-HT1A demonstrated that several unmet needs are still present in the agonism with 5-HT3 antagonism can explain the rapid 5-HT cell treatment of major depression. The “classical” approach adopt- firing induced by vortioxetine compared to SSRIs such as fluox- ed to develop new antidepressants drugs, based on selectivity, etine. Vortioxetine is also able to activate the glutamatergic sys- did not result in increased remission rates in clinical practice, tem in the rat frontal cortex through antagonism at 5-HT3, 5-HT7 whereas multi-modality represents a new approach to develop receptors. All these pharmacological modes of action can con- novel antidepressants endowed with multiple actions that af- tribute to explain the increased clinical efficacy of vortioxetine fect several pharmacological targets. Multimodal antidepres- in the treatment of cognitive symptoms of depression. Cognitive sants, developed in the last three years, act through at least deficits in depression are often associated with both a subopti- two pharmacological modes of action (serotonin reuptake in- mal response to antidepressants and reduced remission rates. hibition, agonist/antagonists on neurotransmitter receptors) on Vortioxetine is the first multimodal antidepressant available for at least two or more pharmacologic targets. Vortioxetine is a the treatment of depression with a specific, positive impact on cognitive symptoms. novel multimodal antidepressant that exerts its antidepressant efficacy in animal models of depression through a combination of two pharmacological modes of action: reuptake inhibition Key words and receptor activity. In vitro studies indicate that vortioxetine is Depression • Serotonin • Multi-modality • Glutamatergic System • Cog- antagonist of 5-HT3, 5-HT7 and 5-HT1D receptors, a partial ago- nitive symptoms • Vortioxetine

Introduction dividuals suffering from depression will undoubtedly increase due to the progressive ageing of the general popu- Depression is one of the most common and invalidating lation. Considering gender, women, especially those with psychiatric disturbances with an incidence of 17-18% an age between 40 and 50 years, are twice as likely to be 1 2 in the general population . In general, depressive dis- affected by depression compared to men 4. orders are characterised by significant burden and have enormous impact on patients. They are thus costly not only in terms of healthcare expenses for pharmacological Unmet needs in the pharmacological therapy and hospitalizations, but also from social, occu- treatment of major depressive disorder pational and personal standpoints. It Italy, at least 1.5 mil- Depression can be diagnosed and treated with pharma- lion individuals suffer from depression, while 10% of the cological therapy, despite data from the WHO indicat- population, or about 6 million individuals, have experi- ing that less than 25% of affected individuals have ac- enced at least one episode of depression during their life- cess to effective treatments. In the last 60 years, a num- time 3. According to the projections of the World Health ber of antidepressants belonging to various classes have Organization (WHO), by 2020 depression will be the been developed, which have allowed for improvements second leading cause of disability worldwide after car- in therapy and prognosis of major depressive disorder diovascular disease. Depressive symptoms are frequent (MDD). Nonetheless, there are still a number of unmet in the elderly (> 65 years), and the number of elderly in- needs including: slow onset of action, sub-optimal effi-

Correspondence Filippo Caraci, Department of Drug Sciences, University of Catania, viale Andrea Doria 6, 95125, Catania, Italy • Tel. +39 0957384028 • Fax +390957384238 • E-mail: [email protected]

210 Journal of Psychopathology 2015;21:210-223 Multi-modality as a new pharmacological approach for treatmentof depression: the role of vortioxetine

cacy, presence of residual symptoms, inefficacy on co- In a prospective clinical study, more than for other symp- morbid cognitive symptoms, treatment of comorbidities, toms, patients complained of the presence of at least one management of elderly patients with depression and cognitive symptom for 94% of the symptomatic period, problems related to tolerability. for 44% of the time during remission and for 66% of the Even if selective serotonin re-uptake inhibitors (SSRIs) time during three-year follow-up 12. and serotonin-norepinephrine reuptake inhibitors (SNRIs) In patients with MDD who respond to therapy with an are generally considered as first-line therapy in the treat- SSRI or SNRI, but who are not in remission, cognitive dys- ment of MDD, according to the guidelines of the Nation- function persisted in 70% of cases with a reduction in al Institute for Health and Care Excellence (NICE), about concentration and/or decision-making 25. In addition, it is 20−30% of patients with depression do not respond to known that tricyclic antidepressants (TCA) have a nega- first-line therapy 7. Many studies have demonstrated that tive effect on cognitive function due to their anticholin- 60-70% of patients respond to initial antidepressant mon- ergic properties 16. Taken together, these data show that otherapy 9, and that more than one-third of patients treat- there is still the need to improve cognitive functioning in ed for depression become resistant to therapy even when patients undergoing treatment with antidepressants. initial treatment was correctly chosen, administered for Another important aspect to consider is that many pa- an adequate length of time and properly dosed 6. The cor- tients cannot tolerate antidepressant therapy due to ad- relation between an inadequate response to initial treat- verse effects. In fact, around 50% of patients discontinue ment and worsening of prognosis necessitates, therefore, antidepressant therapy within 6 months of treatment 17. the identification of new agents that provide better clini- Even if adverse events such as nausea and diarrhoea cal response to initial therapy. can lead to early discontinuation of treatment, these ef- Remission, considered as the primary objective of thera- fects are usually of short duration and resolve after 2-3 py, is defined as a reduction or absence of symptoms for a weeks. However, long-term adverse effects such as sexual prolonged period of time 10. The most common definitions dysfunction, insomnia and weight gain may be present to identify remission in clinical studies are: MADRS ≤ 10, throughout the entire treatment period, and thus have a HAM-D17 total score ≤ 7, or CGI-S ≤ 2. Unfortunately, a significant impact on the quality of life and compliance 18. significant proportion of patients (around 32%) who meet For persistent or severe adverse effects, guidelines rec- criteria for remission continue to show residual symp- ommend dose reduction, switching to an antidepressant toms that are generally more subjective than objective, with less propensity for the side effect in question, non- but which nonetheless have a negative impact on long- pharmacological treatment, or symptomatic treatment 19. term outcomes 8-10. The presence of residual symptoms Nonetheless, the potential benefits of using additional is associated with early recurrence and with a reduction drugs to treat side effects should be evaluated in light of in the quality of life and a greater risk of suicide. In the the added risk in terms of safety and tolerability 20. This STAR-D study, patients who responded to therapy and approach, however, will considerably increase the costs who did not experience remission reported 6-7 residual of therapy. depressive symptoms. The most common included in- Treatment-emergent sexual dysfunction (TESD) caused by somnia (94.6%), sadness (70.8%) and decreased concen- antidepressants is a problem of considerable importance tration (69.6%) 11. that can lead to early discontinuation of therapy. The in- Current treatments help to resolve depressive symptoms cidence of TESD can be as high as 70% depending on in many patients, but in others leave a number of residual the type and duration of antidepressant therapy 22. SSRIs symptoms, especially cognitive symptoms 12. In fact, cog- are associated with a relatively high propensity to cause nitive symptoms have recently been considered as a criti- sexual dysfunction, and for this reason should be used cal factor in persistence of disease and in occupational with caution in patients with pre-existing symptoms re- and social disabilities during MDD 13-15. The association lated to sexual dysfunction as they could be aggravated between cognitive deficits, limitations in functioning and by pharmacological treatment 5. major depressive episodes was highlighted in a survey In some cases SSRIs can cause sleep disturbance in of over 21,000 individuals within the European ESEMeD patients with depression 23. Diverse effects have been study 15. In that study, it was reported a strong association observed with different types of SSRIs: while fluoxetine between major depression and cognitive dysfunction, and paroxetine are known to delay the REM phase and and in particular deficits in concentration and attention. reduce the duration and efficiency of sleep, sertraline Current antidepressants help to improve mood in many is associated with an increase in the duration and ef- patients, but have limited clinical efficacy in the treat- ficiency of sleep and reduced night-time awakenings ment of cognitive symptoms 12 13 16. 23. Among the SNRIs, venlafaxine increases the time of Even if cognitive dysfunction is often unrecognised by the REM sleep, but can reduce the total duration of sleep physician, it is nonetheless worrisome for many patients. 21. It has been demonstrated that sleep-related adverse

211 F. Caraci, G. Di Sciascio

events are the most common cause of discontinuation of get (e.g. serotonin transporter, SERT) has not led to high treatment with SNRIs in adults 23. Early relief of insom- rates of remission in controlled or observational studies. nia in patients with depression, however, can increase Actually, different studies are focused on residual symp- both compliance to treatment and overall functioning, toms, which unfortunately prevent the achievement of while complete resolution of insomnia significantly im- remission in clinical practice. In this regard, increased proves prognosis in MDD 9. attention has also been placed on cognitive symptoms as Weight gain is another common adverse effect that is rare they are frequently present in many forms of depression with acute treatment, while it is more frequent during that show a sub-optimal response to SSRIs and SNRIs. long-term antidepressant therapy. Weight gain is a sig- Such new evidence implicates that compared to a classic nificant problem in terms of tolerability and is associated approach adopted to date with selectivity of intervention with low acceptance to therapy, and consequently with on individual monoaminergic systems, new multimodal a reduction in long-term compliance 24. The incidence approaches are centred on the development of agents of weight gain is 18−50% in patients undergoing antide- having antidepressant activity with multiple mechanisms pressant therapy in open-label clinical studies 18. One of of action and that interact with multiple pharmacologi- the unmet needs in clinical practice is thus the need to cal targets. According to this scenario multimodal anti- develop new antidepressants that have a better tolerabil- depressants can modulate neurotransmitter systems, such ity profile compared to SSRIs and SNRIs, with a lower in- as the glutamatergic, dopaminergic and cholinergic, that cidence of side effects including sexual dysfunction and have not been adequately considered in the treatment of weight gain 37. major depression 30 38 (Table I). Multimodal drugs with antidepressant activity developed in the last few years interact with ≥ 2 pharmacological targets (SERT, 5-HT , New pharmacological targets in treatment 1A 5-HT , 5-HT , 5-HT ) and have more than 2 mechanisms of major depression: a new class 1B 3 7 of multimodal antidepressants of action (serotonin transporter inhibition, agonism/antagonism of ionotrophic and metabotrophic receptors) 38. Treatment of MDD during the last 50 years has been Drug discovery processes in major depression are mainly mainly based on the monoaminergic hypothesis. How- planned to include multiple mechanisms of action in the ever, several lines of evidence have suggested that the same antidepressant in one drug different mechanisms monoamine theory of depression is too simplistic to ex- of drugs as observed in combination therapies in clinical plain a syndrome as complex as depression and the lack practice. Several controlled clinical studies have in fact of clinical remission in up to 60-70% of patients. The lim- demonstrated the possibility of increasing response and itations of the monoaminergic hypothesis have emerged remission rates by combining SSRIs with noradrenaline from preclinical and clinical studies 26. Preclinical studies and dopamine reuptake inhibitors (NDRI) such as bu- demonstrated that delay between the rapid modification propion. However, such advantages were not confirmed at the synaptic level of biogenic amines in the acute phase in the recent CO-MED study when considering the in- and the therapeutic effects seen after at least 3-4 weeks creased risk of adverse events 38 39. cannot be explained only by the decreased expression of Drug discovery processes were initially focused on the tyrosine hydroxylase and β-adrenergic and serotoniner- development of new multimodal antidepressants that gic (5-HT1A) receptors; it is believed that progressive alter- could sinergistically potentiate the three monoaminer- ations of specific signalling pathways (CREB, GSK-3beta, gic systems (5-HT, NA and DA) with triple inhibitors of AKT/mTOR) related to activation of neurotrophic factors monoamine reuptake such as amitifadine, even if pre- (e.g. brain-derived neurotrophic factor, BDNF) leads to registration clinical studies have still not provided defini- a subsequent impairment 27-29. These studies suggest that tive conclusions on the clinical efficacy of these drugs 40. independently of the main ‘monoaminergic’ activity of With the progressive accumulation of new evidence on many currently used antidepressants, in order to be clini- the involvement of other neurotransmitter systems such cally effective these drugs likely interfere with various sig- as the glutamatergic and cholinergic 41, preclinical re- nalling pathways that are downstream of monoaminer- search has focused on the development of the first multi- gic receptors. These include BDNF, mTOR and AKT/GSK modal antidepressant with multiple monoaminergic tar- 3beta signaling pathways, that have driven recent interest gets that can interact with ≥ 2 pharmacological targets in the development of new antidepressants with higher (SERT, 5-HT1A, 5-HT1B, 5-HT3, 5-HT7) and have more than rates of clinical remission 29 30. 2 mechanisms of action (serotonin transporter inhibition, Recent evidence, starting with the STAR-D study, has agonism/antagonism of receptors) 38 (Table I). demonstrated that there are still many unmet needs in In the development process, this approach has been pharmacological treatment of MDD. An approach based largely conservative by attempting to maintain the clini- on ‘selectivity’ focused on a single pharmacological tar- cal benefits of SERT inhibition but including at the same

212 Multi-modality as a new pharmacological approach for treatmentof depression: the role of vortioxetine

time other pharmacological targets such as 5-HT1A recep- Table I. tors in order to reduce the slow onset of action and im- Potential advantages of a multimodal approach in the phar- prove upon the tolerability profile (and in particular sexu- macological treatment of major depression. I possibili vantaggi al dysfunction). Vilazadone was the first effort to develop dell’approccio multimodale nel trattamento farmacologico del- a multimodal antidepressant whose pharmacodynamic la depressione maggiore. profile includes inhibition of SERT and partial agonism of 5-HT (Fig. 1). However, the initial clinical benefits • Combination of multiple mechanisms of action in a single 1A antidepressant observed in terms of reduction of the onset of clinical • Inclusion of new pharmacological targets and interaction action were not confirmed in later studies, and this drug with other neurotransmitter systems (e.g., glutamatergic was also found to be associated with gastrointestinal ad- system) in addition to monoaminergic systems (SERT in- 42 43 verse effects . hibition) Vortioxetine is the latest candidate among multimodal • Possibility to treat residual symptoms such as cognitive antidepressants. Its pharmacodynamic profile includes symptoms which are frequent depressed patients with a not only inhibition of SERT and partial agonism on suboptimal response to SSRIs and SNRIs • Possibility to use antagonistic activity on receptors in- 5-HT1A, but also antagonism on 5-HT3 and 5-HT7 receptors that allows, for the first time, indirect intervention on volved in adverse effects (e.g. 5-HT3) and consequent im- the glutamatergic system of the prefrontal cortex which provement of the tolerability profile to date has not been targeted with currently used antidepressants. The development of multimodal antidepressants in recent based on mechanism of action, and not only on the use years, and in particular vortioxetine, has been improved of the older nomenclature based on ATC categories and in parallel with advances in understanding the neurobio- approved indications. For example, antidepressants are logical basis of depression (“the glutamatergic hypoth- effective not only in treatment of major depression, but esis of depression”). In addition, classification systems also in anxiety disorders. At the same time, antipsychotics of psychotropic drugs have been revised in the attempt are used in the treatment of bipolar disorder and not only to renew these systems with new evidence in neurosci- in psychoses due to their diverse mechanism of action ence, also considering of the wide spectrum of use of and neurobiological activity profile. The older ATC no- psychotropic drugs in clinical practice if referred to their menclature, therefore, does not describe all the potential approved indications. clinical applications of this class of drugs 44. In the last two years, different studies have been carried In accordance with the new classification (neuroscience- out at the ECNP (European College of Neuropsychophar- based nomenclature) recently presented at Berlin at the macology) by Joseph Zohar, David Nutt, Guy Goodwin, 27th Congress of the European College of Neuropsychop- in collaboration with Stephen Stahl (International College harmacology (18-21 October 2014), every psychotropic of Neuropsychopharmacology) and the American College drug can be classified according to the following 4 axes: of of Neuropsychopharmacology (Pierre Blier and David • Axis 1: Pharmacologic target and mechanism of ac- Kupfer) in order to propose a new classification system tion. This axis reflects current knowledge of molecular

Vilazodone Vortioxetine

SERT SHT1A SERT 5-HT1A

5-HT1B Multimodal Multimodal 2 pharmacological targets 6 pharmacological targets and 2 5-HT1D and 2 mechanisms of action mechanisms of action (activity on (activity on receptors + receptors + inhibition of reuptake) 5-HT3 inhibition of reuptake)

5-HT7

Figure 1. Examples of multimodal antidepressants. Esempi di antidepressivi multimodali.

213 F. Caraci, G. Di Sciascio

targets and pharmacology and the most accepted hy- toninergic system (extracellular accumulation of 5-HT) in potheses on its mechanism of action; addition to that produced by inhibition of SERT 48. More-

• Axis 2: Approved indications. Reports the current over, in the initial design of the molecule 5-HT1B agonism therapeutic indications of the drug approved by regu- was not anticipated, which was later revealed to be im- latory authorities (FDA, EMA); portant for potentiating the SSRI action of vortioxetine in • Axis 3: Efficacy and tolerability. Summarise the evi- animal models of depression, and especially antagonism

dence on clinical efficacy and most frequent clinical of 5-HT7 receptors that no other antidepressant had. This uses, in addition to its tolerability profile and most rendered vortioxetine unique compared with other anti- common adverse effects; depressants as a possible positive, indirect modulator of • Axis 4: Neurobiological activity. Describes the main the glutamatergic system 46. preclinical pharmacology of the drug and primary Following the drug discovery process, the pharmacody- neurobiological activity on different neurotransmit- namic profile of vortioxetine was characterised by an el- ter systems. In addition, this axis reports, whenever evated potential to inhibit SERT with an affinity similar to available, relevant clinical data obtained in phase I/ escitalopram (1.6 nM vs 10 nM), along with intrinsic full

II studies. agonist activity for 5-HT1A receptors, partial agonist activ- 45 According to this new nomenclature , recent neuro- ity for 5-HT1B receptors and antagonist activity for 5-HT1D, 46 47 49 biological understanding of several neuropsychiatric 5-HT3 and 5-HT7 receptors (Table 2, Figure 2) . disorders and on the neurobiological activity profile of If the pharmacodynamic profile and functional activity different psychotropic drugs can be combined in a new of vortioxetine is compared in rats and humans it can be system based on mechanism of action that better corre- observed that vortioxetine has affinity binding values that sponds to a dimensional approach for a more appropri- are similar for the different types of receptors with the ex- ate clinical use. ception of 5-HT1A and 5-HT7 where the affinity is higher In this new scenario, multimodal antidepressants, and in in humans (Table II). Preclinical pharmacological studies particular vortioxetine, represent a novel opportunity for have considered this difference relevant and adopted a pharmacological treatment of major depression in light of range of doses starting with 0.5 mg/kg, a dose that corre- preclinical and clinical efficacy and possible mechanism sponds, after an acute treatment in rats, to an occupation of action on multiple psychopathological dimensions of 5-HT3 and 5-HT1D receptors and 50% of SERT, up to (mood, anxiety, cognition) in combination with a good doses of 5-10 mg/kg in which vortioxetine fully occupies 46 tolerability profile. the 5-HT1B, 5-HT1A and 5-HT7 receptors . Knowledge of the pharmacodynamic profile of vortiox- To describe the pharmacodynamic profile of vortioxetine etine thus represents an essential step in understanding it is necessary to consider the contribution of serotoner- the potential advantages of a multimodal approach in gic receptors, and in particular 5-HT1A, 5-HT3 and 5-HT7, pharmacological treatment of depression and the poten- in order to explain the broad spectrum of efficacy of the tial use of this drug in clinical practice. drug not only in classic animal models of depression, but also in newer preclinical models in which currently-available SSRIs are not efficacious 46. 5-HT receptors have an Pharmacodynamic profile of vortioxetine: 1A important role in clinical response to antidepressants in from development to new pharmacologcal 50 targets treatment of major depression . As already mentioned, preclinical studies have demonstrated that the difference Vortioxetine is an example of a multimodal antidepres- in the onset of therapeutic action and the rapid modifica- sant that, in addition to classic inhibition of SERT, is also a tion at the synaptic level of biogenic amines in the acute full agonist of 5-HT1A receptors, partial agonist of 5-HT1B phase observed after 3-4 weeks cannot be explained by receptors and an antagonist of 5-HT1D, 5-HT3 and 5-HT7 down-regulation of 5-HT1A receptors alone, but with the receptors (Fig. 1). The drug discovery of vortioxetine is progressive alteration of other specific signaling pathways a good example of innovation and serendipity. The ini- (CREB, GSK-3beta, AKT/mTOR), the increased release of tial objective in the development of vortioxetine was to neurotrophic factors (e.g. BDNF) and the consequent ef- develop a lead compound that combined SERT inhibi- fects on synaptic plasticity 47 51 52. tion with: 1) 5-HT1A agonism to reduce the slow onset of 5-HT1A receptors are a subgroup of receptors localised clinical action and minimise side effects related to sexual at the somatodendritic level of serotonergic neurons that dysfunction; 2) antagonism of 5-HT3 to reduce nausea, a originate at the level of the raphe nuclei as well as at the frequent side effect with SSRIs during the first few weeks presynaptic level in the terminations of serotonergic neu- of treatment 46 47. rons at different areas of the CNS, such as the hippocam- During development of vortioxetine it was observed that pus and prefrontal cortex. At the somatodendritic level,

5-HT3 antagonism led to further potentiation of the sero- 5-HT1A receptors inhibit firing of serotonergic neurons;

214 Multi-modality as a new pharmacological approach for treatmentof depression: the role of vortioxetine

53 54 table II. . It has been hypothesize that the antagonism on pr- Multimodal activity of vortioxetine: differences in affinity esynaptic 5-HT1D receptors, included in the mechanism of between humans and rats. L’attività multimodale di action of vortioxetine, could contribute to the potentiation vortioxetina: le differenze di affinità tra uomo e ratto. of the serotonergic system since it is known that selective

antagonists of 5-HT1D receptors potentiate the increase in Affinity (nM) extracellular levels of 5-HT induced by SSRIs 55. Receptor Rat Human It has been demonstrated that the effects of vortioxetine on serotonergic neurons of the raphe depend signifi- 5-HT3 1.1 3.7 46 5-HT 190 19 cantly on antagonism of 5-HT3 receptors . It is already 7 well-known that the combination of 5-HT receptor an- 5-HT 230 15 3 1A tagonists with SSRIs potentiates the extracellular increase 5-HT1B 16 33 in serotonin in the prefrontal cortex and ventral hip-

5-HT1D 3,7 54 pocampus compared with a single treatment with SSRI 48 SERT 8,6 1,6 . It has also been demonstrated in rats that agonists of 5-HT3 receptors such as SR57227 prevent the rapid re- activation of the serotonergic system observed after a long-term administration of vortioxetine at a dose of 5 desensitization and especially down-regulation of 5-HT1A receptors is crucial for the clinical efficacy of antidepres- mg/kg 53. These pharmacological effects of vortioxetine sants 50. In the first phase of treatment with SSRI antide- observed in animal models could lead to a better tolerability profile during the first week of treatment with a pressants, 5-HT1A receptors are stimulated by elevated levels of 5-HT with consequent inhibition of firing and reduction in anxiety symptoms associated with inhibition the possible presence of anxiety symptoms. In succession, of the serotonergic system induced by SSRIs during the first days of treatment. 5-HT1A receptors undergo progressive desensitisation and especially down-regulation with consequent recovery A specific feature of the pharmacodynamic profile of vor- and a successive increase in firing of serotonergic neu- tioxetine is the ability to indirectly potentiate the activity rons. Vortioxetine, due to the combination of full agonism of other neurotransmitter systems involved in the patho- genesis of major depression such as the noradrenergic, of 5-HT1A and antagonism of 5-HT3 together with classic dopaminergic, cholinergic, and in particular the gluta- SERT inhibition, leads to rapid desensitization of 5-HT1A receptors with rapid activation of the serotonergic system matergic system; a major pharmacological target recently compared to SSRIs such as fluoxetine (24 h vs 7 days) 46 studied for the treatment of depression (Fig. 3). Vortioxetine significantly increases the extracellular levels of noradrenaline (NA) in the prefrontal medial cortex and ventral hippocampus following acute or chronic administration in rats 54. It is interesting to note that vortioxetine is not associated with a significant inhibition of the noradrenaline transporter (NAT) at either the level of the central or peripheral nervous system; it does not increase the peripheral levels of NA as observed with SNRI antidepressants, which through NET inhibition, can favour the onset of adverse effects such as tachycardia and an increase in arterial blood pressure 57 58. Recent evidence suggests that vortioxetine indirectly potentiates the NA system at the medial prefrontal cortex and ventral hip-

pocampus due to antagonism of 5-HT3 combined with 46 agonism of 5-HT1A receptors . Antagonism on 5-HT3 receptors leads to a reduced release NA in the locus coeruleus along with a reduced activation of inhibitory

presynaptic α2 receptors and the following increase in firing of noradrenergic neurons starting from the locus coeruleus with a concomitant release of NA in the pre-

frontal cortex and hippocampus. The agonism on 5-HT1A Figure 2. receptors contributes to potentiation of this effect as it Pharmacodynamic profile of vortioxetine. Profilo leads to an increase in the extracellular levels of NA in farmacodinamico di vortioxetina. the same areas 46 58.

215 F. Caraci, G. Di Sciascio

Figure 3. Vortioxetine, due to its agonist activity on 5-HT1A receptors, also leads to an increase in the extracellular levels of Direct and indirect effects of vortioxetine on neurotransmitter dopamine (DA) in the medial prefrontal cortex at a dose systems. Effetti diretti e indiretti di vortioxetina sui sistemi of 5 mg/kg, while it does not influence the activity of the neurotrasmettitoriali. mesolimbic dopaminergic system or the release of DA in the nucleus accumbens 46 54. Moreover, vortioxetine, in addition to its activity on monoaminergic systems, increases the release of acetylcholine and histamine in the medial prefrontal cortex (Fig. 3).

Interaction between the serotonergic and glutamatergic systems: the specific role of vortioxetine The glutamatergic system plays an essential role in the pathophysiology of major depression and in the patho- genesis of cognitive symptoms in depression 59 60. The glutamatergic system is considered a relevant pharmacological target for the development of new antidepressants with a better pharmacodynamic profile, especially in the management of treatment-resistant depression 30 59. In major depression, it has been demonstrated a dysfunc- SERT: serotonin transporter; 5-HT: serotonin; ACh: acetylcholine; tion of the glutamatergic system consisting of hyperacti- Hist: histamine; NA: noradrenaline; DA: dopamine. vation of ionotropic NMDA receptors for glutamate with an increased release of glutamate correlated with acute stress and possible neurodegenerative phenomena in the the serotonergic system has an essential role in modula- 28 29 prefrontal cortex and hippocampus . It has also been tion of the glutamatergic system. Multimodal antidepres- shown that first and second generation antidepressants sants such as vortioxetine can modulate the glutamatergic can reduce the release of glutamate, especially after acute system through interaction with serotonergic receptors stress, and that they can reduce glutamatergic transmis- including 5-HT , 5-HT , 5-HT and 5-HT which can sion at the levels of NMDA receptors, potentiating AMPA 1A 1B 3 7 regulate the neurobiological effects of the serotonergic receptors 28. system on the glutamatergic system. The discovery of the rapid antidepressant action of keta- Recent studies suggest that vortioxetine, through an- mine, a non-competitive antagonist of NMDA receptors, tagonism of 5-HT and 5-HT receptors, exerts a positive in patients with treatment-resistant depression has opened 3 7 modulation on the glutamatergic system in the prefrontal new avenues for the identification of new pharmacologi- cortex. This action may lead to an increase in clinical ef- cal targets and developing new antidepressants that can directly or indirectly modulate the glutamatergic system 61. ficacy when treating residual symptoms, such as cognitive Ketamine is an effective drug for therapy of treatment-re- symptoms, which are often present in patients with subop- sistant depression, although it is associated with psychoto- timal or inadequate response to antidepressants finally pre- mimetic effects (hallucinations and perception disorders) venting the achievement of complete remission in clinical 61 62 and has a high potential for abuse as highlighted by several practice . Similar to ketamine, vortioxetine also selec- studies 29. Moreover, it has been demonstrated that abuse tively activates the Akt/mTOR pathway, unlike SSRIs which of ketamine may also lead to comprised cognitive func- inactivate it. Of interest, the Akt/mTOR pathway has an es- tion and alteration in thought content 29. Considering these sential role in mediating the synaptic and neurotropic ef- aspects, it is clear that ketamine cannot be readily used fects of ketamine 29 63. Moreover, it has been hypothesized in clinical practice due to issues regarding tolerability and that vortioxetine, through antagonism of 5-HT3 receptors safety. It is thus necessary to develop new antidepressants expressed on dendrites of GABAergic neurons, reduces with serotoninergic action that can also indirectly modu- the inhibition exerted by 5-HT3 on pyramidal glutamater- late the glutamatergic system 61. gic neurons in the prefrontal cortex and at the same time The serotonergic system influences the glutamatergic sys- inhibits the activity of GABAergic neurons at the level of 61 tem through 5-HT1A, 5-HT1B, 5-HT3 and 5-HT7 receptors. CA1 region of the hippocampus .

Ketamine loses its antidepressant efficacy in animal mod- In addition, prolonged antagonism on 5-HT3 receptors els following depletion of serotonin, which suggests that leads to the induction of long-term potentiation (LTP), one

216 Multi-modality as a new pharmacological approach for treatmentof depression: the role of vortioxetine

of the most important molecular and cellular phenomena Preclinical efficacy of vortioxetine in animal underlying learning and memory, as recently observed models of depression with vortioxetine in ex vivo hippocampal studies in rats 64. These studies showed for the first time that vortioxetine In recent years, vortioxetine has been extensively studied prevents the increase of inhibitory postsynaptic currents in animal models of depression, and has shown efficacy as 46 induced by serotonin at the level of pyramidal cells in an antidepressant in rodents in the range of 1-10 mg/kg . the CA1 region of the hippocampus and enhances LTP, This has been demonstrated following acute administra- events that are not modified by treatment with SSRIs such tion in classic behavioural tests such as the forced swim as escitalopram 64. Augmentation of LTP by vortioxetine test (both in mice and in Flinders sensitive line rats), the rat also stimulated neurogenic processes in the subgranular social interaction test and the novelty-suppressed feeding 65 zone of the dentate gyrus in mice within 14 days of treat- test . The efficacy of vortioxetine in these animal models ment in contrast to that observed with fluoxetine, which is based on the monoamine hypothesis even after 14-21 65 leads to proliferation and differentiation of neural precur- days of treatment , and is also efficacious in animal mod- sors after only 21 days of treatment 65. It is interesting to els of depression in which SSRIs are ineffective. In particu- note that vortioxetine, after 14 days at a dose of 20 mg/ lar, it has been demonstrated that vortioxetine is effective 69 kg, also leads to significant increases of dendrites lenght in C57 mice that do not respond to SSRIs and in an ani- and dendritic connections, which are likely related to the mal model based on the GABAergic hypothesis of depres- selective activation of the AKT/mTOR pathway. sion known as progesterone withdrawal. In this model, the Finally, vortioxetine enhances the glutamatergic system abrupt discontinuation of progesterone administration in at the level of the prefrontal cortex and hippocampus the rat following a long-term treatment (21 days) leads to 61 the onset of anxiety, irritability and a depressive phenotype through antagonism on 5-HT7 receptors . 5-HT7 receptors are located on the soma and the presynaptic terminals with anhedonia and social withdrawal. The administration of glutamatergic pyramidal neurons that project from the of vortioxetine has an antidepressant effect as measured prefrontal cortex to the raphe nuclei, from which seroton- by the forced swim test, in contrast to that observed with fluoxetine or duloxetine in this model 70 71. ergic neurons originate. Moreover, 5-HT7 receptors are expressed on GABAergic interneurons at the level of the Due to its multimodal action and its ability to interact prefrontal cortex and hippocampus. The antagonism on with multiple targets, vortioxetine has an antidepressant effect in animal models after a sub-chronic treatment at 5-HT7 receptors by vortioxetine directly on glutamatergic neurons of the prefrontal cortex leads to an enhancement a dose of 5 mg/kg, a dose that is associated with only a of glutamatergic transmission towards the raphe nuclei partial occupation of SERT (40%). It can be hypothesize, 61 with a subsequent activation of serotonergic neurons . in fact, that agonism on 5-HT1A receptors in combination with antagonism on 5-HT receptors, is essential for in- In animal models, it is known that 5-HT7 antagonists 3 enhance the response to SSRIs and improve memory creasing the efficacy of vortioxetine compared with SSRIs and executive functioning in models of cognitive dys- in animal models where SSRIs and SNRIs are ineffective. function induced by the administration of competitive In recent years, research in psychopharmacology has fo- antagonists of NMDA receptor such as MK-801 or ad- cused on improving the translational value of animal stud- dictive substances such as phencyclidine 61 66. It is in- ies with the aim of developing a model with an increased teresting to note that in these animal models synergistic predictive value 30. The main problem, in fact, is that of efficacy was seen by combining SSRIs with selective reproducing, within the limits of the large differences be- 67 5-HT7 antagonists . Importantly, vortioxetine combines tween rodents and humans, behavioural phenotypes that both of these pharmacodynamic properties in the same have the same neurobiological basis of symptoms such as molecule. cognitive deficits (attention, memory and executive func- Taken together, the effects of vortioxetine on the gluta- tioning) that still represent the most relevant unmet needs matergic system, neurogenic processes and synaptic in the pharmacological treatment of depression. plasticity can explain its clinical efficacy in both animal models of depression and in cognitive dysfunction in de- Animal models of cognitive dysfunction: pressed patients with cognitive deficits 62 or suboptimal 68 the unique mechanism of action response to SSRIs . In particular, the positive modula- of vortioxetine tion of the glutamatergic system in the prefrontal cortex, through antagonism of 5-HT3 and 5-HT7 receptors, is as- Vortioxetine is the first example of an antidepressant that sociated with an increased clinical efficacy compared to has been widely studied not only in animal models of SSRIs in the treatment of residual symptoms such as cog- depression, but also in all the newer models of cognitive nitive symptoms that prevent the achievement of func- dysfunction (and in particular attention, memory and ex- tional remission in clinical practice. ecutive functioning) where SSRIs such as fluoxetine and

217 F. Caraci, G. Di Sciascio

escitalopram are ineffective 72. It is interesting to note that SNRIs such as duloxetine are not able to ‘correct’ memory the increased spectrum of preclinical efficacy of vortiox- deficits induced by serotonin depletion 75. Therefore, oc- etine in animal models of depression was also seen in cupation of SERT does not seem to be relevant in ‘rescu- terms of clinical efficacy in treatment of cognitive deficits ing’ cognitive deficits in animal models, and the multi- in MDD 62. Among the main mechanisms involved in this modal activity of vortioxetine acquires provides an added effect, it is believed that enhancement of the choliner- value when considering its pharmacodynamic profile 46 75. gic and glutamatergic systems in the hippocampus and Moreover, in adult rats, vortioxetine is associated with re- activation of the dopaminergic system in the prefrontal covery of learning that has been compromised by treat- cortex arising from the multimodal action of vortioxetine ment with selective inhibitors of tryptophan hydroxylase are most relevant since these neurotransmitters have a or exposition to chronic stress (i.e. cold) 76. Lastly, admin- role in cognitive functions such as attention, memory and istration of vortioxetine for 4 weeks in older C57BL/6 mice executive functioning 46 72. Study of EEG patterns in ro- (12 months) leads to improvements in visuospatial mem- dents has confirmed that there are relevant differences ory, whereas fluoxetine, even at high doses, is ineffective between vortioxetine and second-generation antidepres- in the same model 69. sants (SSRIs and SNRIs) in terms of general neurobiologi- Vortioxetine has also been demonstrated to be effective cal effects, and in particular on the state of vigilance 72. in a preclinical rat model of dysfunction of attention and Quantitative analysis of the EEG in the prefrontal cortex executive function induced by subchronic administra- in rodents has a good translational value and is a validat- tion of phencyclidine (PCP, 5 mg/kg for 7 days) 46. This is ed method to predict EEG patterns in man 72. It is known, an important model for validation of the hypothesis that in fact, that the activity on theta and gamma waves is the glutamatergic action of vortioxetine is relevant to its directly correlated with memory encoding and retrieval, action. In the PCP model, in fact, the glutamatergic sys- whereas alpha and gamma waves are mostly associated tem is compromised at the level of the prefrontal cortex. with attention 73. A close correlation between the antide- Vortioxetine is able to revert these effects, resulting in pressant effects in the quantitative analysis of EEG at the improvement in tests of attention and executive function prefrontal cortex and the effects of these drugs on cogni- even at a dose of 3 mg/kg administered either chronically tive function has been demonstrated 72. In particular, it or acutely 46 77. has been observed in rats that vortioxetine, even at a dose Overall these data (Table III) can explain why the broad of 5 mg/kg administered in acute (corresponding to 80% spectrum of preclinical efficacy seen with vortioxetine in occupation of SERT), is associated with a completely dif- animal models of cognitive dysfunction are confirmed in ferent EEG pattern than either escitalopram (2 mg/kg) or controlled clinical studies where vortioxetine has been duloxetine (10 mg/kg) administered at doses that lead to shown to be effective in treatment of cognitive deficits in 80% occupation of SERT (and thus equivalent doses in major depression 62. preclinical terms) 72. Vortioxetine increases the activity of alpha, theta and gamma by 25-60%, in contrast to escit- Pharmacokinetic profile of vortioxetine alopram and duloxetine which reduce their activity. The authors of that study also demonstrated that the effects Pharmacokinetic studies in healthy volunteers in pre- of vortioxetine are mediated by the 5-HT1A, 5-HT3 and registration studies showed that vortioxetine has a linear 73 5-HT7 receptors . These data, together with that of Dale pharmacokinetics over a wide dose range from 2.5-60 et al. 64 on the enhancement of LTP, can explain the ef- mg/day following a single administration 78. Vortioxetine fects of vortioxetine in animal models of cognitive dys- has a half-life of 66 hours and steady-state plasma levels function 72. are reached in about 2 weeks (12-14 days). The absolute In fact, vortioxetine has been demonstrated to potentiate bioavailability of vortioxetine is 75% after oral adminis- processes of acquisition and retention of memory (includ- tration and its absorption is not influenced by food. In ing visuospatial) in many rodent models 46 72. In particular, addition, vortioxetine shows an high level of plasma pro- vortioxetine reverts memory deficits in the rat induced by teins binding (98%; Table IV) 79. serotonin depletion following administration of selective The main pharmacokinetic parameters of vortioxetine 74 75 inhibitors of tryptophan hydroxylase . The effects of are a Tmax of 7-8 hours (time needed to reach a maximal vortioxetine have been observed in the novel object rec- plasma concentration after a single administration) and ognition test even at low doses (0.1 mg/kg) in which 80% a Cmax of 9 ng/ml after a dose of 5 mg/day and 33 ng/ml of 5-HT3 receptors are blocked. In the same animal mod- after a dose of 20 mg/day (Table IV). The starting dose is el, the authors demonstrated that the pro-cognitive action 10 mg/day in a single administration with the possibil- of vortioxetine is related not only to antagonism of 5-HT3 ity to increase the dose to 20 mg/day after one week of 74 receptors, but also to agonism of 5-HT1A receptors . In treatment, or reduce it to 5 mg/day depending on the in- the same animal model, SSRIs such as escitalopram and dividual response 79.

218 Multi-modality as a new pharmacological approach for treatmentof depression: the role of vortioxetine

Vortioxetine is metabolized by oxidation via multiple pharmacological interactions is therefore needed on the CYP450 isozymes (CYP2D6, 3A4/5, 2C19, 2C9 and 2B6) basis of the available evidence 82. SSRIs an heterogene- and the following conjugation with glucuronic acid 80. ous class of antidepressants with substantial differences CYP2D6 is the major isoenzyme involved in the phase I in pharmacodynamics and pharmacokinetics. Some SS- metabolism of vortioxetine 81. Plasma concentrations of RIs such as fluoxetine, paroxetine and fluvoxamine can vortioxetine are about twice in CYP2D6 poor metaboliz- modify the plasma concentrations of other psychotropic ers compared to extensive metabolizers 79. The maximum drugs by inhibiting CYP450 isoenzymes, thus causing dose in poor metabolizers is 10 mg/day. The metabolites clinically-relevant pharmacological interactions 82. of vortioxetine [main metabolite 3-methyl-4-(2-piperazine- According to this scenario, vortioxetine has an advantage 1-yl-phenylsulphanyl)-benzoic acid] do not have antide- compared to SSRIs because it does not modify the ac- pressant activity, do not cross the blood-brain barrier and tivity of CYP450 isoenzymes, and thus does not cause are thus not pharmacologically relevant 46. No relevant dif- clinically-relevant pharmacological interactions 60. It is ferences have been observed in the main pharmacokinetic nonetheless important to specify that inhibitors of CY- parameters in relation to gender or in the presence of re- P2D6 such as bupropion or inhibitors of CYP3A4 such as duced hepatic or renal function 79. fluconazole and ketoconazole can increase the AUC and

It is important to underline that vortioxetine, in contrast Cmax of vortioxetine (respectively +128% and 114% for to several SSRIs (fluoxetine, paroxetine, fluvoxamine) and bupropion, +46% and +15% for fluconazole, +30% and SNRIs (duloxetine), does not inhibit several isoenzymes +26% for ketoconazole) 60. However, these interactions of CYP450 (CYP2D6, 3A4/5, 2C19, 2C9) and thus does are not clinically relevant considering the broad thera- not have any clinically relevant drug interactions. peutic index of vortioxetine, even if in such cases appro- Polypharmacy is a common and frequent practice in priate dose reduction of vortioxetine should be consid- psychiatry due to treatment of comorbidities or as add- ered in case of interaction with inducers of CYP3A4 such on therapy. The availability of different classes of drugs as rifampicin that reduce the AUC and Cmax (respectively has also increased the probability of pharmacodynamic -73% and -51%); in this case a dose increase of vortiox- and pharmacokinetic interactions with consequent risk etine can be considered 81. of morbidity and mortality, especially in the elderly Overall these data suggest that vortioxetine has a fa- population. Detailed knowledge of clinically-significant vourable pharmacokinetic and tolerability profile char-

TabLE III. Summary of evidence in preclinical studies 25 41. Sommario delle evidenze negli studi di farmacologia preclinica 25 41.

Target Action Results in preclinical models

5-HT3 Antagonism Increase in the effects of SSRIs / SNRIs Enhancement of extracellular increase of 5-HT in the medial prefrontal cortex and ventral hippocampus compared to monotherapy with SSRI in rats Increase in extracellular levels of noradrenaline in the medial prefrontal cortex and ventral hippocampus in rats Positive modulation of the glutamatergic system in the prefrontal cortex Inhibition of GABAergic neurons at CA1 in the hippocampus of rats and augmentation of LTP Procognitive effects in rats depleted of 5-HT and improvements in memory and executive function

5-HT7 Antagonism Antidepressant and anxiolytic properties Potentiation of the antidepressant effects of SSRIs in animal models of depression Positive modulation of the glutamatergic system in the prefrontal cortex Improvement of memory and executive function in animal models of cognitive dysfunction

5-HT1D Antagonism Enhancement of the extracellular increase of 5-HT compared to monotherapy with SSRIs

5-HT1B Partial agonism Potentiation of the antidepressant effects of SSRIs in animal models of depression

5-HT1A Agonism Antidepressant and anxiolytic properties

Acceleration of desensitization of somatodendritic 5-HT1A autoreceptors with a more rapid reac- tivation of the serotonergic system in animal models Increase in extracellular levels of dopamine and noradrenaline in the medial prefrontal cortex Procognitive effects in rats following depletion of 5-HT SERT Inhibition Antidepressant and anxiolytic properties in animal models

219 F. Caraci, G. Di Sciascio

TabLE IV. Pharmacokinetic profile of vortioxetine. Profilo farmacocinetico di vortioxetina.

Parameter Vortioxetine Oral bioavailability 75% Half-life 66h

Tmax 7-8h

Cmax 9 ng/ml (5 mg/die); 18 ng/ml (10 mg/die) 33 ng/ml (20 mg/die) Plasma binding 98% Metabolism CYP2D6, 3A4/5, 2C19, 2C9 and 2B6 Drug interactions Vortioxetine does not inhibit CYP450 isozymes and does not have any pharmacologically relevant drug interactions Does reduction is needed in case of co-administration with bupropion, fluconazole or ketoconazole, while dose increase may be needed in case of co-administration with rifampicin Starting dose 10 mg/die Dose adjustments Can be increased (up to 20 mg/day) or decreased (5 mg/day) after 1 week Administration Once daily

acterized by the absence of sexual adverse events and cognition) together with a good tolerability profile charc- weight gain 79. terized by the absence of sexual adverse effects without a significant weight gain 46 79. Conclusions Conflict of interests Multimodal antidepressants are a new psychopharmaco- Filippo Caraci, in relation to the issues treated in the last three logical tool for the treatment of major depression. This years, was a consultant and/or speaker at symposia organized new pharmacological class includes agents with antide- by Lundbeck, Eli-Lilly, Otuska, Grunenthal, Janssen. pressant activity which have multiple mechanisms of ac- Guido Di Sciascio received grant for participation in Advisory Board sponsored by Angelini, Otsuka, Lilly and Polifarma. tion. These drugs interact with multiple pharmacological targets thereby modulating several neurotransmitter systems that have not been addressed until now in treatment References of major depression, such as glutamatergic, dopaminer- 1 Murray CJ, Lopez AD. Evidence-based health policy – Les- gic and cholinergic systems. Vortioxetine is an example sons from the Global Burden of Disease Study. Science of a multimodal antidepressant that, in addition to classic 1996;274:740-3. inhibition of SERT, also acts as a full agonist on 5-HT 1A 2 Murray C J, VosT Lozano et al. Disability-adjusted life years receptors, partial agonist on 5-HT1B receptors and antago- (DALYs) for 291 diseases and injuries in 21 regions, 1990- nist on 5-HT1D, 5-HT3 and 5-HT7 receptors. 2010: a systematic analysis for the Global Burden of Disease All the evidence presented in this review that vortioxetine Study 2010. Lancet 2012;380:2197-223. has a broad spectrum of efficacy not only in classic ani- 3 Battaglia A, Dubini A, Mannheimer R. Depression in the mal models of depression, but also in all the newer animal Italian community: epidemiology and socio-economic im- models of cognitive dysfunction (especially memory and plications. Int Clin Psychopharmacol 2004;19:135-42. executive function). In particular, vortioxetine is the first 4 Kessler RC, Berglund P, Demler O, et al. The epidemiol- example of a multimodal antidepressant that, due to its ogy of major depressive disorder: results from the Na- multiple mechanisms of action in addition to SERT inhibi- tional Comorbidity Survey Replication (NCS-R). JAMA tion, has been shown to be effective in all animal mod- 2003;289:3095-105. els of depression and cognitive dysfunction where SSRIs 5 Bauer M, Whybrow PC, Angst J, et al. World Federation of such as fluoxetine and escitalopram and SNRIs such as Societies of Biological Psychiatry (WFSBP) guidelines for duloxetine are ineffective 46. The multiple pharmacologi- biological treatment of unipolar depressive disorders, part cal effects of vortioxetine associated with a multimodal 1: acute and continuation treatment of major depressive dis- approach provide a broad profile of clinical efficacy on order. World J Biol Psychiatry 2002;3:5-43. multiple psychopathological dimensions (mood, anxiety, 6 Fava M1, Davidson KG. Definition and epidemiology of

220 Multi-modality as a new pharmacological approach for treatmentof depression: the role of vortioxetine

treatment-resistant depression. Psychiatr Clin North Am 22 Montejo AL, Llorca G, Izquierdo JA, et al. Incidence of 1996;19:179-200. sexual dysfunction associated with antidepressant agents: 7 NICE. Depression: the treatment and management of de- a prospective multicenter study of 1022 outpatients. J Clin pression in adults. Leicester, UK: British Psychological Soci- Psychiatry 2001;62:10-21. ety 2010. 23 Ferguson JM. SSRI antidepressant medications: adverse ef- 8 Nierenberg AA, Wright E. Evolution of remission as the new fects and tolerability. Prim Care Companion J Clin Psychia- standard in the treatment of depression. J Clin Psychiatry try 2001;3:22. Supplement 1999;60:7-11. 24 Westenberg H, Sandner C. Tolerability and safety of flu- 9 Thase ME, Sloan DM, Kornstein SG. Remission as the criti- voxamine and other antidepressants. Int J Clin Pract cal outcome of depression treatment. Psychopharmacol 2006;60:482-91. Bull 2002;36:12-25. 25 McClintock SM, Husain MM, Wisniewski SR, et al. Residual 10 Kelsey JE. Clinician perspective on achieving and maintain- symptoms in depressed outpatients who respond by 50% ing remission in depression. J Clin Psychiatry 2001;62 (Sup- but do not remit to antidepressant medication. J of Clin Psy- pl 26):16-21. chopharmacol 2013;31:180-6. 11 Rush AJ, Trivedi M, Wisniewski S, et al. Acute and longer- 26 Caraci F, Copani A, Nicoletti F, Drago F. Depression and term outcomes in depressed outpatients requiring one or Alzheimer’s disease: neurobiological links and common several treatment steps: a STAR* D report. Am J Psychiatry pharmacological targets. Eur J Pharmacol 2010;626:64-71. 2006;163:1905-17. 27 Krishnan V, Nestler EJ. The molecular neurobiology of de- 12 Conradi H, Ormel J, de Jonge P. Presence of individual pression. Nature 2008;455:894-902. (residual) symptoms during depressive episodes and peri- 28 Musazzi L, Treccani G, Mallei A, Popoli M. The action ods of remission: a 3-year prospective study. Psychol Med of antidepressants on the glutamate system: regulation of 2011;41:1165-1174. glutamate release and glutamate receptors. Biol Psychiatry 13 McIntyre RS, Cha DS, Soczynska JK, et al. Cognitive deficits 2013;73:1180-8. and functional outcomes in major depressive disorder: de- 29 Kristal JH, Sanacora G, Duman RS. rapid rapid-acting gluta- terminants, substrates, and treatment interventions. Depress matergic antidepressants: the path to ketamine and beyond. Anxiety 2013;30:515-27. Biol Psychiatry. 2013;73:1133-41. 14 Jaeger J, Berns S, Uzelac S, et al. Neurocognitive deficits 30 O’Leary OF, Dinan TG, Cryan JF. Faster, better, stronger: and disability in major depressive disorder. Psychiatry Res Towards new antidepressant therapeutic strategies. Eur J 2006;145:39-48. Pharmacol 2014:S0014-2999(14)00584-6. 15 Buist-Bouwman MA, Ormel J, de Graaf R, et al. Mediators 31 Papakostas GI, Petersen T, Denninger JW, et al. Psychosocial of the association between depression and role functioning. functioning during the treatment of major depressive disorder Acta Psychiatr Scand 2008;118:451-8. with fluoxetine. J Clin Psychopharmacol 2004;24:507-11. 16 Biringer E, Rongve A, Lund A. A review of modern antide- 32 Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and long- pressants effects on neurocognitive function. Curr Psychia- er-term outcomes in depressed outpatients requiring one or try Rev 2009;5:164-74. several treatment steps: a STAR*D report. Am J Psychiatry 17 Hunot VM, Horne R, Leese MN, Churchill RC. A cohort 2006;163:1905-17. study of adherence to antidepressants in primary care: 33 Trivedi MH, Fava M, Wisniewski SR, et al. Medication aug- the influence of antidepressant concerns and treatment mentation after the failure of SSRIs for depression. N Engl J preferences. Prim Care Companion J Clin Psychiatry Med 2006;354:1243-52. 2007;9:91-9. 34 Silverstein B, Patel P. Poor response to antidepressant medi- 18 Sherman C. Long-term side effects surface with SSRIs. Clin cation of patients with depression accompanied by somat- Psychiatry News 1998;26:1-3. ic symptomatology in the STAR*D Study. Psychiatry Res 19 Anderson IM, Ferrier IN, Baldwin RC, et al. Evidence-based 2011;187:121-4. guidelines for treating depressive disorders with antidepres- 35 Stein DJ. Depression, anhedonia, and psychomotor symp- sants: a revision of the 2000 British Association for Psychop- toms: the role of dopaminergic neurocircuitry. CNS Spectr. harmacology guidelines. J Psychopharmacol 2008;22:343-96. 2008;13:561-5. 20 Lam RW, Kennedy SH, Grigoriadis S, et al. Canadian net- 36 Barnhart WJ, Makela EH, Latocha MJ. SSRI-induced apathy work for mood and anxiety treatments (CANMAT) clini- syndrome: a clinical review. J Psychiatr Pract 2004;10:196-9. cal guidelines for the management of major depressive 37 disorder in adults. III. Pharmacotherapy. J Affect Disord Baldwin DS, Foong T. Antidepressant drugs and sexual dys- 2009;117:S26-43. function. Br J Psychiatry 2013;202:396-7. 38 21 Luthringer R, Toussaint M, Schaltenbrand N, et al. A double- Richelson E. Multi-modality: a new approach for the treat- blind, placebo-controlled evaluation of the effects of orally ment of major depressive disorder. Int J Neuropsychophar- administered venlafaxine on sleep in inpatients with major macol 2013;30:1-10. depression. Psychopharmacol Bull 1996;32(4):637-46.*** 39 Rush AJ, Trivedi MH, Stewart JW et al. Combining medi-

221 F. Caraci, G. Di Sciascio

cations to enhance depression outcomes (CO-MED): acute multimodal antidepressant, produces regionally selective and long-term outcomes of a single-blind randomized study. increases of multiple neurotransmitters-a rat microdialysis Am J Psychiatry 2011;168:689-701. and electrophysiology study. Eur Neuropsychopharmacol 40 Tran P, Skolnick P, Czobor P et al. Efficacy and tolerabil- 2013;23:133-45. 55 ity of the novel triple reuptake inhibitor amitifadine in the Pullar IA, Boot JR, Broadmore RJ et al. The role of the 5-HT1D treatment of patients with major depressive disorder: a ran- receptor as a presynaptic autoreceptor in the guinea pig. Eur domized, double-blind, placebo-controlled trial. J Psychiatr J Pharmacol 2004;493:85-93. Res 2012;46:64-71. 56 Stahl SM, Grady MM, Moret C, Briley M. SNRIs: their 41 Maletic V, Robinson M, Oakes T et al. Neurobiology of de- pharmacology, clinical efficacy, and tolerability in com- pression: an integrated view of key findings. Int J Clin Pract parison with other classes of antidepressants. CNS Spectr 2007;61:2030-40. 2005;10:732-47. 42 Rickels K, Athanasiou M, Robinson DS et al. Evidence for 57 Siepmann T, Ziemssen T, Mueck-Weymann M, et al. The efficacy and tolerability of vilazodone in the treatment of effects of venlafaxine on autonomic functions in healthy vol- major depressive disorder: a randomized, double-blind, unteers. J Clin Psychopharmacol 2007;27:687-91. placebo-controlled trial. J Clin Psychiatry 2009;70:326-33. 58 Suwabe A, Kubota M, Niwa M, et al. Effect of a 5-HT(1A) 43 Laughren TP, et al. Vilazodone: clinical basis for the US receptor agonist, flesinoxan, on the extracellular noradrena- Food and Drug Administration’s approval of a new antide- line level in the hippocampus and on the locomotor activity pressant. J Clin Psychiatry 2011;72:1166-73. of rats. Brain Res 2000;858:393-401. 44 Zohar J, Nutt DJ, Kupfer DJ et al. A proposal for an updated 59 Sanacora G, Treccani G, Popoli M. Towards a glutamate neuropsychopharmacological nomenclature. Eur Neuropsy- hypothesis of depression: an emerging frontier of neuropsychopharmacol 2014;24:1005-14. chopharmacology for mood disorders. Neuropharmacology 45 Zohar j, Stahl S, Möller HJ et al. Neuroscience-based No- 2012;62:63-77. menclature. 1st Edition. Cambridge: Cambridge University 60 Duman RS, Li N, Liu RJ, et al. Signaling pathways underlying Press 2014. the rapid antidepressant actions of ketamine. Neurophar- 46 Sanchez C, Asin KE, Artigas F. Vortioxetine, a novel antidepres- macology 2012;62:35-41. sant with multimodal activity: Review of preclinical and clin- 61 Pehrson AL, Sanchez C. Serotonergic modulation of gluta- ical data. Pharmacol Ther 2014;pii:S0163-7258(14)00127. mate neurotransmission as a strategy for treating depression 47 Bang-Andersen B., Ruhland T, Jorgensen M. et al. Discovery and cognitive dysfunction. CNS Spectr 2014;19:121-33. of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu 62 McIntyre RS, Lophaven S, Olsen CK. A randomized, double- AA21004): a novel multimodal compound for the treatment blind, placebo-controlled study of vortioxetine on cognitive of major depressive disorder. J Med Chem 2011;54, 3206-21 function in depressed adults. Int J Neuropsychopharmacol 48 Mork, A, Pehrson A, Brennum, LT et al. Pharmacological 2014;17:1557-67. effects of Lu AA21004: a novel multimodal compound for 63 Du Jardin KG, Liebenberg N, Muller H et al. Single dose vor- the treatment of major depressive disorder. J Pharmacol Exp tioxetine or ketamine but not fluoxetine increases expression Ther 2012;340:666-75. of neuroplasticity related genes in the rat prefrontal cortex. 49 Westrich, L., Pehrson, A., Zhong, H. et al. In vitro and in Eur Neuropsychopharmacol 2013;23(S2):S392. vivo effects of the multimodal antidep ressant vortioxe- 64 Dale E, Zhang H, Leiser SC, et al. Vortioxetine disinhibits tine (Lu AA21004) at human and rat targets. Int J Psychiatry pyramidal cell function and enhances synaptic plasticity in Clin Pract 2012;16(Suppl. 1): 47. the rat hippocampus. J Psychopharmacol 2014;28:891-902. 50 65 Albert PR, François BL. Modifying 5-HT1A receptor gene ex- Guilloux JP, Mendez-David I, Pehrson A, et al. Antidepres- pression as a new target for antidepressant therapy. Front sant and anxiolytic potential of the multimodal antidepres- Neurosci 2010;4:35. sant vortioxetine (Lu AA21004) assessed by behavioural 51 Calabrese F, Molteni R, Racagni G, Riva MA. Neuronal plas- and neurogenesis outcomes in mice. Neuropharmacology ticity: a link between stress and mood disorders. Psycho- 2013;73:147-59. neuroendocrinology 2009;34 (Suppl 1):S208-16. 66 Bonaventure P, Kelly L, Aluisio L, et al. Selective blockade 52 Fumagalli F, Racagni G, BrunelloN. Farmaci per il tratta- of 5-hydroxytmusaryptamine (5-HT)7 receptors enhances mento dei disturbi affettivi. In: Rossi F., Cuomo V, Riccardi 5-HT transmission, antidepressant-like behavior, and rapid C, editors. Farmacologia. Principi di base e applicazioni ter- eye movement sleep suppression induced by citalopram in apeutiche. 2th ed. Torino:,Edizioni Minerva Medica 2011, rodents. J Pharmacol Exp Ther 2007;321:690-8. pp. 232-46. 67 Nikiforuk A. Selective blockade of 5-HT7 receptors facili- 53 Betry C, Pehrson A L, Etievant A et al. The rapid recovery of tates attentional set-shifting in stressed and control rats. Be- 5-HT cell firing induced by the antidepressant vortioxetine hav Brain Res 2012;226:118-23. involves 5-HT(3) receptor antagonism. Int J Neuropsychop- 68 Montgomery SA, Nielsen RZ, Poulsen LH et al. A ran- harmacol 2013;16,1115-27. domised, double-blind study in adults with major depressive 54 Pehrson AL, Cremers T, Betry C, et al. Lu AA21004, a novel disorder with an inadequate response to a single course of

222 Multi-modality as a new pharmacological approach for treatmentof depression: the role of vortioxetine

selective serotonin reuptake inhibitor or serotonin-noradren- 75 Jensen JB, du Jardin KG, Song D et al. Vortioxetine, but not aline reuptake inhibitor treatment switched to vortioxetine escitalopram or duloxetine, reverses memory impairment or agomelatine. Hum Psychopharmacol 2014, doi:10.1002/ induced by central 5-HT depletion in rats: evidence for di- hup.2424. rect 5-HT receptor modulation. Eur Neuropsychopharmacol 69 Li Y, Sanchez C, Gulinello M. Memory impairment in old 2014;24:148-59. mice is differentially sensitive to different classes of antide- 76 Wallace A, Pehrson AL, Sánchez C, et al. Vortioxetine re- pressants. Eur Neuropsychopharmacol 2013;23(S2):S282. stores reversal learning impaired by 5-HT depletion or 70 Li Y, Pehrson AL, Budac D, et al. A rodent model of premen- chronic intermittent cold stress in rats. Int J Neuropsychop- strual dysphoria: progesterone withdrawal induces depres- harmacol 2014;17:1695-706. sion-like behavior that is differentially sensitive to classes of 77 Waller JA, Pehrson AL, Sanchez C. Vortioxetine modulates antidepressants. Behav Brain Res 2012;234:238-47. GABA and glutamate marker expression in a subchronic 71 Li Y, Raaby KF, Sánchez C et al. Serotonergic receptor PCP model of impaired executive functioning in rats. Euro- mechanisms underlying antidepressant-like action in the pean Neuropsychopharmacology 2014;24:S470-1. progesterone withdrawal model of hormonally induced de- 78 Areberg J, Sogaard B, Hojer AM. The clinical pharmacokinet- pression in rats. Behav Brain Res 2013;256:520-8. ics of Lu AA21004 and its major metabolite in healthy young 72 Pehrson AL, Leiser SC, Gulinello M et al.. Treatment of cog- volunteers. Basic Clin Pharmacol Toxicol 2012;111:198-205. nitive dysfunction in major depressive disorder-a review of 79 Citrome L. Vortioxetine for major depressive disorder: a sys- the preclinical evidence for efficacy of selective serotonin tematic review of the efficacy and safety profile for this new- reuptake inhibitors, serotonin-norepinephrine reuptake in- ly approved antidepressant - what is the number needed to hibitors and the multimodal-acting antidepressant vortiox- treat, number needed to harm and likelihood to be helped etine. Eur J Pharmacol 2014;pii:S0014-2999(14)00582-2. or harmed? Int J Clin Pract 2014;68:60-82. 73 Leiser SC, Pehrson AL, Robichaud PJ, Sanchez C. Multi- 80 Hvenegaard MG, Bang-Andersen B, Pedersen H et al. Identi- modal antidepressant vortioxetine increases frontal cortical fication of the cytochrome P450 and other enzymes involved oscillations unlike escitalopram and duloxetine--a quantita- in the in vitro oxidative metabolism of a novel antidepressant, tive EEG study in rats. Br J Pharmacol 2014;171:4255-72. Lu AA21004. Drug Metab Dispos 2012;40:1357-65. 81 74 du Jardin KG, Jensen JB, Sanchez C, et al. Vortioxetine dose- Chen G, Lee R, Højer AM et al. Pharmacokinetic drug inter- dependently reverses 5-HT depletion-induced deficits in actions involving vortioxetine (Lu AA21004). A multimodal spatial working and object recognition memory: a potential antidepressant. Clin Drug Investig 2013;33:727-36. role for 5-HT1A receptor agonism and 5-HT3 receptor an- 82 Spina E, Trifiro G, Caraci F. Clinically significant drug interac- tagonism. Eur Neuropsychopharmacol 2014;24,160-71. tions with newer antidepressants. CNS Drugs 2012;26:39-67.

223 EDITORIA PER LA CLASSE MEDICA PER L’AGGIORNAMENTO PROFESSIONALE

MANUALE DI PSICHIATRIA TERRITORIALE A cura di Giuseppe Nicolò e Enrico Pompili

49-,00 euro

MANUALE DI FARMACOTERAPIA PSICHIATRICA A cura di Roberto Brugnoli e Paolo Girardi

24,00 euro

LA FOLLIA MANIACO-DEPRESSIVA Emil Kraepelin Edizione italiana curata Roberto Brugnoli, Paolo Girardi, Lorenzo Mazzarini

Traduzione di Matteo Elis Landricina

Formato pdf 8,00 euro Print on demand 16,00 euro COLLANA DI PSICHIATRIA DIRETTA DAL PROF. GIRARDI DAL PROF. DIRETTA COLLANA DI PSICHIATRIA

AcquistAli su www.pAcinimedicinA.it